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COMPLETE LEARNING NOTE: ANAESTHETICS — GENERAL AND LOCAL

From Absolute Beginner to MBBS Examination Mastery

Source: Morgan and Mikhail's Clinical Anesthesiology, 7e | Barash, Cullen and Stoelting's Clinical Anesthesia, 9e | Miller's Anesthesia, 10e

SECTION 1: BIG PICTURE OVERVIEW

What Problem Does Anaesthesia Solve?

Imagine you need surgery. The surgeon needs to cut through your skin, muscles, and organs. Without intervention, this would be unbearably painful, you would move uncontrollably, and the emotional trauma would be overwhelming.

Anaesthesia solves this by doing one or more of these things:

Making you completely unconscious (so you do not know what is happening) - General Anaesthesia
Blocking all nerve signals from a region of your body (so you feel nothing, but you remain awake) - Local/Regional Anaesthesia

There are four things a perfect anaesthetic should achieve. Doctors call this the "TETRAD OF ANAESTHESIA":

Component	What it means in simple language
Analgesia	No pain
Unconsciousness	The patient is "asleep" and unaware
Muscle relaxation	The muscles are relaxed so the surgeon can work
Suppression of reflexes	The body does not react to the surgical stimuli

No single drug does ALL four perfectly. This is why anaesthesia is almost always a combination of multiple drugs - called BALANCED ANAESTHESIA.

SECTION 2: BUILD THE FOUNDATION

Part A: The Nervous System - The Target of All Anaesthetics

Before any drug makes sense, you need to understand what it is acting on.

The Neuron - The Basic Unit

Think of a neuron (nerve cell) as a long wire that carries electrical messages. The message travels along the wire and at the end, it tells another cell what to do - for example: "CONTRACT!" (muscle) or "FEEL PAIN!" (brain).

That electrical message is called an ACTION POTENTIAL.

How does an action potential work? (Step by step)

At rest, the inside of a nerve is negatively charged (-60 to -70 millivolts). This is called the resting membrane potential.

A sodium-potassium pump (Na⁺-K⁺-ATPase) works continuously to:

Push 3 sodium (Na⁺) ions OUT of the cell
Pull 2 potassium (K⁺) ions INTO the cell

This creates a concentration gradient - lots of Na⁺ outside, lots of K⁺ inside. The membrane is more "leaky" to K⁺ than Na⁺, so K⁺ leaks out, leaving the inside negatively charged.

The sequence of an action potential:

RESTING STATE
Inside of nerve = -70 mV
Na⁺ channels CLOSED
         ↓
STIMULUS arrives (pain, touch, cut)
         ↓
Voltage-gated Na⁺ channels OPEN
Na⁺ rushes INTO the cell (following concentration gradient)
         ↓
Inside goes from -70 mV → +35 mV (DEPOLARIZATION)
         ↓
Na⁺ channels automatically CLOSE (inactivate)
K⁺ channels open, K⁺ rushes OUT
         ↓
Membrane returns to -70 mV (REPOLARIZATION)
         ↓
Na⁺-K⁺ pump restores normal ion distribution
         ↓
NEXT section of nerve depolarizes → signal travels along nerve

This is exactly what LOCAL ANAESTHETICS interfere with.

Types of Nerve Fibres - A Critical Table

Different nerve fibres carry different types of messages, and they have different sensitivities to local anaesthetics:

Fibre Type	What it carries	Diameter	Speed	Myelinated?	Sensitivity to LA
Aα	Motor (movement), Proprioception	12-20 μm	70-120 m/s	Yes	Low
Aβ	Touch, Pressure	5-12 μm	30-70 m/s	Yes	Moderate
Aγ	Motor (muscle spindle)	3-6 μm	15-30 m/s	Yes	Moderate
Aδ	Pain (sharp, fast), Temperature	2-5 μm	12-30 m/s	Yes	High
B	Preganglionic autonomic	<3 μm	3-14 m/s	Some	High
C	Pain (slow, burning), Temperature	0.4-1.2 μm	0.5-2 m/s	NO	Moderate-High

Clinical Pearl: The order of block by local anaesthetics is: Autonomic → Sensory → Motor

This means a patient receiving a spinal anaesthetic will first lose their blood pressure control (autonomic), then feel numbness (sensory), and last lose ability to move (motor). Recovery happens in the reverse order.

Part B: Consciousness and the Brain - The Target of General Anaesthesia

What is Consciousness?

Consciousness is your awareness of yourself and your surroundings. It depends on normal function of the Reticular Activating System (RAS) in the brainstem, which keeps the cortex "awake."

General anaesthetics work by suppressing activity in the RAS and throughout the central nervous system. When CNS activity is suppressed sufficiently, you become unconscious.

Key molecular targets of general anaesthetics:

GABA-A receptors (most important): These are inhibitory receptors. When activated, they let chloride (Cl⁻) into the neuron, making it harder to fire. Most IV anaesthetics (propofol, barbiturates, benzodiazepines) enhance GABA-A function - they make the brain's "brake system" more powerful.
NMDA receptors (glutamate receptors): These are excitatory receptors. Ketamine BLOCKS these - so ketamine works by blocking the brain's "accelerator."
Potassium channels, sodium channels, and others: Inhaled anaesthetics have multiple targets.

Simple analogy:

GABA-A drugs = stepping on the brake pedal
NMDA blockers = cutting the fuel line to the accelerator
Result either way = the car (brain) slows down and stops

Part C: Stages of General Anaesthesia (Guedel's Classification)

Arthur Guedel described four stages in 1937 based on observations with ether anaesthesia. Modern anaesthesia moves through these so fast you barely see them, but examiners love them:

STAGE I - Analgesia (Induction)

Patient is conscious but feels less pain
Reflexes intact
Can still talk and respond
Like being tipsy

STAGE II - Excitement/Delirium

Loss of consciousness but reflexes are exaggerated
Irregular breathing, breath-holding
Vomiting and laryngospasm can occur
MOST DANGEROUS STAGE - must pass through quickly
Like being very drunk and uncontrolled

STAGE III - Surgical Anaesthesia (the target) Divided into 4 planes:

Plane 1: Regular breathing, eyes moving
Plane 2: Eyes fixed, eyeball reflexes begin to disappear
Plane 3: Intercostal paralysis begins, diaphragmatic breathing
Plane 4: Diaphragm paralysis, respiratory arrest imminent

STAGE IV - Medullary Depression (Overdose)

Cessation of respiration and cardiovascular collapse
Death if not treated

Memory trick for stages: "AESM" - Analgesia, Excitement, Surgical, Medullary depression

SECTION 3: GENERAL ANAESTHETICS - INHALATIONAL AGENTS

What Are Inhalational Anaesthetics?

These are drugs that are inhaled as gases or vapours. They enter via the lungs, dissolve into the blood, travel to the brain, and cause unconsciousness.

They are the oldest anaesthetics. Ether and chloroform were used from the 1840s. Modern agents are halothane, isoflurane, desflurane, sevoflurane, and nitrous oxide.

The Key Concept: MAC (Minimum Alveolar Concentration)

Definition of MAC: The alveolar (lung air) concentration of an inhaled anaesthetic that prevents movement in 50% of patients in response to a standardised stimulus (such as a surgical skin incision).

Why MAC matters:

It is the measure of POTENCY for inhalational agents
A drug with a LOW MAC is very potent (you need very little of it)
A drug with a HIGH MAC is less potent (you need a lot of it)
MAC is like the ED50 for inhalational agents

Analogy: Think of MAC like the "strength" of coffee. A very strong coffee (like espresso) only needs 1 shot to wake you up (low MAC). A weak coffee needs many cups (high MAC).

Factors that INCREASE MAC (you need more drug):

Childhood (children need higher MAC)
Hyperthermia
Hyperthyroidism
Chronic alcohol abuse
Drug tolerance

Factors that DECREASE MAC (you need less drug):

Old age
Hypothermia
Hypothyroidism
Pregnancy
Acute alcohol intoxication
Opioids, sedatives (additive CNS depression)
Anaemia, hypoxia, hypotension

MAC values to memorize:

Agent	MAC (%)	Solubility (blood:gas coefficient)
Nitrous oxide (N₂O)	105%	0.47 (very LOW = fast)
Halothane	0.75%	2.4 (moderate)
Isoflurane	1.15%	1.4
Sevoflurane	2%	0.65 (LOW = fast)
Desflurane	6-7%	0.42 (very LOW = fastest)

Note on N₂O: MAC of 105% means you would need a concentration greater than 100% (impossible to breathe pure N₂O - no oxygen) to achieve surgical anaesthesia. So N₂O can NEVER be used alone for surgical anaesthesia. It is always supplemental.

Blood:Gas Solubility Coefficient - Explained Simply

This number tells you how soluble the drug is in blood compared to air.

Low coefficient (like desflurane 0.42): The drug does NOT like to dissolve in blood. It stays mostly in the gas phase. This means:
- It reaches the brain QUICKLY (fast induction)
- It leaves the brain QUICKLY (fast emergence/waking up)
High coefficient (like halothane 2.4): The drug LOVES to dissolve in blood. A large amount must dissolve in blood before the brain concentration rises enough. This means:
- Induction is SLOW
- Emergence is SLOW

Analogy: Think of the blood as a sponge. A drug with a high solubility = blood acts like a giant sponge and absorbs lots before the brain even gets any. Takes long to fill the sponge, takes long to wring it out (emergence). A drug with low solubility = blood barely absorbs it, so it quickly reaches the brain.

INDIVIDUAL INHALATIONAL AGENTS

1. NITROUS OXIDE (N₂O) - "Laughing Gas"

Properties:

Colourless gas at room temperature, stored as liquid in cylinders
Sweetish smell
MAC = 105% (cannot produce full anaesthesia alone)

Mechanism:

NMDA receptor antagonist (blocks glutamate excitatory receptors)
Also acts on opioid receptors (hence its analgesic effect)

Uses:

Supplemental anaesthesia (combined with other agents)
Dental procedures (anxiolytic + analgesic)
Labour analgesia (Entonox = 50% N₂O + 50% O₂)

Advantages:

Excellent analgesia
Rapid onset and offset
Minimal cardiovascular depression
Does NOT cause malignant hyperthermia

The Second Gas Effect: When N₂O is used with another inhaled agent, the rapid uptake of N₂O into blood speeds up the uptake of the second gas (e.g., halothane). This accelerates induction. Like drafting behind a truck on a highway.

Diffusion Hypoxia (Fink Effect): When N₂O is stopped at end of anaesthesia, it rapidly leaves the blood into the alveoli and DILUTES the oxygen in the lungs, briefly dropping oxygen concentration. This causes temporary hypoxia. To prevent: Give 100% oxygen for 5-10 minutes at the END of anaesthesia.

DANGER - Closed Space Expansion: N₂O moves into air-containing spaces more quickly than nitrogen can leave. This means:

Middle ear pressure rises
Pneumothorax expands
Bowel gas expands
Pneumocephalus worsens
Air emboli enlarge Contraindications: Bowel obstruction, pneumothorax, middle ear surgery, air embolism

Vitamin B12 Inactivation: Prolonged exposure to N₂O (>6 hours in operating theatre personnel or >24 hours in patients) irreversibly oxidises vitamin B12 (cobalamin). This inhibits methionine synthetase, an enzyme that requires B12.

Result: Cannot make myelin properly
Complications: Megaloblastic anaemia, subacute combined degeneration of the spinal cord (peripheral neuropathy)

2. HALOTHANE

Properties:

Volatile liquid, non-flammable (unlike ether)
Sweet odour, non-irritating
MAC = 0.75%

Mechanism:

Enhances GABA-A receptor function
Inhibits NMDA receptors

Pharmacokinetics:

Blood:gas coefficient = 2.4 (relatively HIGH = slower onset/offset)
Metabolised in liver (~20% of absorbed dose)

Cardiovascular effects (IMPORTANT for exams):

Reduces cardiac output and myocardial contractility (negative inotrope)
Bradycardia (sensitises SA node to vagal tone)
Sensitises the myocardium to catecholamines - IMPORTANT: risk of ventricular arrhythmias if adrenaline (epinephrine) is used concurrently (e.g., in local anaesthetic solutions by surgeons)
Vasodilation → hypotension

Respiratory effects:

Bronchodilator (good for asthma)
Dose-dependent respiratory depression

Halothane Hepatitis - A CRITICAL EXAM TOPIC:

There are TWO types:

Type	Incidence	Mechanism	Timing	Severity
Type 1 (Mild)	~20% of patients	Non-immune, direct hepatotoxicity, metabolite-mediated	Days after exposure	Mild, self-limiting
Type 2 (Severe = "Halothane Hepatitis")	1 in 35,000	Immune-mediated - trifluoroacetyl chloride metabolite forms antigens on liver proteins → immune attack	2-14 days after second exposure	Fulminant liver failure, death possible

Risk factors for severe hepatitis: Repeated exposures at short intervals, middle-aged obese women, familial predisposition

Malignant Hyperthermia: Halothane triggers malignant hyperthermia (MH) in susceptible patients. This is a life-threatening emergency.

3. ISOFLURANE

Properties:

Non-flammable volatile liquid
Pungent odour (airway irritant - NOT suitable for inhalation induction)
MAC = 1.15%

Mechanism: Enhances GABA-A receptors

Cardiovascular effects:

Reduces systemic vascular resistance (vasodilation) → blood pressure drops
Heart rate increases (reflex tachycardia)
Less myocardial depression than halothane
Does NOT sensitise myocardium to catecholamines as much as halothane

"Coronary Steal" Controversy: Isoflurane dilates coronary arteries. In theory, this could "steal" blood from areas supplied by fixed stenoses (coronary steal phenomenon). However, this is clinically controversial and considered of limited importance.

Advantages:

More stable cardiac rhythm than halothane
Less liver toxicity (only 0.2% metabolised, vs 20% for halothane)
Better muscle relaxation

4. DESFLURANE

Properties:

Very low blood:gas coefficient = 0.42 (LOWEST of all volatile agents) → FASTEST induction and emergence
High MAC = 6-7%
Very pungent - causes coughing, laryngospasm, bronchospasm on inhalation induction (NOT suitable for mask induction, especially in children)
Boiling point very close to room temperature - requires a heated vaporiser

Clinical Use: Maintenance only (not induction), preferred for:

Outpatient (day surgery) procedures - fast waking up
Obese patients (very low fat solubility = less accumulation)

Cardiovascular effects:

Rapid increases in desflurane concentration → transient but significant increases in heart rate, blood pressure, and catecholamine levels (sympathetic activation). More pronounced than with isoflurane.

5. SEVOFLURANE

Properties:

Low blood:gas coefficient = 0.65 (second fastest after desflurane)
Low MAC = 2%
Non-pungent, pleasant odour - IDEAL for inhalation induction, especially in children
Non-irritating to airways

Compound A: Sevoflurane reacts with soda lime (CO₂ absorbent in anaesthesia circuit) to produce Compound A, a potentially nephrotoxic substance in rats. Clinical significance in humans is debated and considered low at normal flow rates.

Clinical advantages:

Best agent for inhalation induction in children and adults
Fast onset and offset
Good cardiovascular stability

COMPARISON TABLE: INHALATIONAL AGENTS

Property	N₂O	Halothane	Isoflurane	Desflurane	Sevoflurane
MAC (%)	105	0.75	1.15	6-7	2
Blood:gas coefficient	0.47	2.4	1.4	0.42	0.65
Speed of onset	Fast	Slow	Medium	Fastest	Fast
Cardiac depression	Mild	Significant	Moderate	Minimal	Minimal
Liver toxicity	None	YES (hepatitis)	Minimal	Minimal	Minimal
Malignant hyperthermia	No	YES	YES	YES	YES
Good for induction	Yes	Yes	No (pungent)	No (pungent)	YES (best)
Metabolised (%)	0.004%	20%	0.2%	0.02%	3-5%

SECTION 3B: GENERAL ANAESTHETICS - INTRAVENOUS AGENTS

Why Use IV Agents?

IV agents work much faster than inhaled agents. Injection → bloodstream → brain in ~30 seconds. This is why anaesthesia is usually INDUCED with an IV agent and then MAINTAINED with an inhalational agent.

1. PROPOFOL (2,6-diisopropylphenol)

Mechanism: Enhances GABA-A receptor function → potentiates chloride influx → hyperpolarisation → CNS depression

Formulation: White emulsion in soybean oil and egg lecithin (looks like "milk"). This is why it is called "milk of anaesthesia." Patients with egg or soy allergy - use caution.

Pharmacokinetics:

Onset: 30-60 seconds
Duration: 5-10 minutes (single dose)
Eliminated by redistribution (from brain to muscle/fat) and then hepatic metabolism
Extremely high protein binding (~97%)

Unique properties:

Antiemetic - dramatically reduces postoperative nausea and vomiting (PONV). Mechanism unclear.
Antipruritic - relieves itching from spinal opioids
Sub-anaesthetic doses = conscious sedation (used for endoscopy, ICU sedation)
Pain on injection (due to emulsion vehicle) - can be reduced by lidocaine pretreatment

Cardiovascular effects:

Dose-dependent hypotension (reduces systemic vascular resistance AND myocardial contractility)
Reflex tachycardia may occur

Respiratory effects:

Apnoea on induction (common)
Reduces laryngeal reflexes (useful for LMA insertion without paralysis)

PROPOFOL INFUSION SYNDROME (PRIS) - High-yield exam topic:

Rare but life-threatening complication
Occurs with HIGH DOSE or PROLONGED infusion (>48 hours in ICU)
Mechanism: Impairs mitochondrial electron transport chain and fatty acid oxidation
Features: Metabolic acidosis, rhabdomyolysis, renal failure, hyperkalaemia, cardiac failure (BRASH-like picture), lipemic plasma, elevated triglycerides
More common in children and patients receiving catecholamines or corticosteroids
Prevention: Limit dose to <4 mg/kg/h; avoid prolonged infusions in children

Uses:

Induction and maintenance of anaesthesia (TIVA - Total IV Anaesthesia)
Conscious sedation
ICU sedation (short term)
Anti-emetic (sub-anaesthetic doses)

2. THIOPENTAL (Thiopentone) - A Barbiturate

Mechanism: Enhances GABA-A receptor function (prolongs chloride channel opening time). At high doses, directly opens Cl⁻ channel.

Properties:

Sodium salt dissolved in water (highly alkaline pH ~10.5)
Yellow powder reconstituted to 2.5% solution
Extremely lipid soluble → VERY rapid onset (arm-brain circulation time ~30 seconds)

Pharmacokinetics:

Onset: <30 seconds
Duration after SINGLE DOSE: 5-15 minutes (due to REDISTRIBUTION, not metabolism)
- Drug leaves brain rapidly, going to muscle then fat
- This is what terminates the effect - NOT metabolism
Metabolism: Slow hepatic metabolism

Cumulation: With repeated doses or infusion, fat stores become saturated and the drug cannot redistribute from the brain anymore. Recovery becomes prolonged. This is why thiopental is NOT used for maintenance of anaesthesia.

Cardiovascular effects:

Myocardial depression
Vasodilation → hypotension
Tachycardia (reflex)

Neuroprotection: Reduces cerebral metabolic rate and ICP (useful in head injury patients, status epilepticus)

Antianalgesic effect: Small doses INCREASE pain sensitivity (hyperalgesia). This is the opposite of an analgesic effect - unique to barbiturates.

Contraindications:

Acute intermittent porphyria - ABSOLUTE CONTRAINDICATION - thiopental induces delta-aminolevulinic acid synthase, the key enzyme in porphyrin synthesis, precipitating a porphyric crisis (severe abdominal pain, motor neuropathy, psychosis)
History of hypersensitivity

Arterial injection: Thiopental is highly irritant. Accidental intra-arterial injection causes vasospasm, gangrene. This is a medical emergency.

SAFE agents in porphyria: Propofol, ketamine, nitrous oxide, opioids

3. KETAMINE

The Dissociative Anaesthetic - A Unique Drug

Mechanism:

Primary: NMDA receptor antagonist (blocks excitatory glutamate receptors)
Also acts on opioid receptors, muscarinic receptors

What "Dissociative" means: Ketamine produces a trance-like state where the patient appears awake (eyes may be open, reflexes largely intact) but is completely unresponsive to pain. It's like the brain and the body are "disconnected" - hence "dissociative."

Unique cardiovascular effects - The OPPOSITE of all other anaesthetics: Most anaesthetics cause cardiovascular depression. Ketamine STIMULATES the cardiovascular system:

Increases heart rate, blood pressure, and cardiac output
Mechanism: Stimulates sympathetic nervous system (releases catecholamines from nerve terminals)
This makes ketamine the DRUG OF CHOICE in shock, hypovolaemia, haemodynamically unstable patients, and trauma

Bronchodilator: Ketamine relaxes bronchial smooth muscle → useful in status asthmaticus, asthmatic patients

Increases ICP: Due to cerebral vasodilation and increased cerebral blood flow

Contraindicated in head injury, raised ICP, hypertensive crisis

Preserves airway reflexes (relatively)

But this can be misleading - aspiration CAN still occur

Analgesia: Excellent analgesic at sub-anaesthetic doses (used for procedural sedation - burn wound dressing, orthopaedic manipulation)

Adverse effects:

Emergence delirium (dysphoria, hallucinations, vivid dreams) on waking up. More common in adults than children. Prevented/reduced by concurrent benzodiazepine (midazolam).
Hypersalivation (give atropine as premedication)
Nystagmus (eye flickering)
Transient mild respiratory depression

Key clinical uses:

Induction in haemodynamically unstable patients (trauma, shock, burns)
Procedural sedation and analgesia
Paediatric anaesthesia (IM route possible)
Status asthmaticus
War/field anaesthesia (can be given IM)

4. ETOMIDATE

Mechanism: Enhances GABA-A receptor function

Unique property: Most haemodynamically stable induction agent - minimal effect on blood pressure or heart rate. Excellent for:

Cardiac patients
Patients with poor cardiac function
Haemodynamically unstable patients (when ketamine is not appropriate)

Adverse effects:

Adrenocortical suppression (inhibits 11β-hydroxylase and 17α-hydroxylase) - even a SINGLE DOSE can suppress cortisol production for 6-8 hours
This is why etomidate is NOT recommended for ICU sedation infusions
Pain on injection
Myoclonus (involuntary muscle jerking) on induction
Nausea and vomiting
Does NOT provide analgesia

5. BENZODIAZEPINES (Midazolam, Diazepam, Lorazepam)

Mechanism: Enhance GABA-A receptor function (increase frequency of Cl⁻ channel opening in response to GABA)

Midazolam is the most commonly used in anaesthesia:

Water-soluble at acidic pH (in the syringe), becomes lipid-soluble at physiological pH (in the body)
Half-life: ~2 hours (shorter than diazepam)
Excellent anxiolysis (anti-anxiety) and amnesia (patient won't remember pre-op period)

Uses in anaesthesia:

Premedication (anxiolysis + anterograde amnesia)
Induction (alone or combined)
Conscious sedation
Prevention of ketamine emergence delirium

Reversal: Flumazenil - a competitive antagonist at GABA-A benzodiazepine receptor

Note: Flumazenil has a short half-life. Resedation can occur after flumazenil wears off.

6. OPIOIDS IN ANAESTHESIA

Opioids are not anaesthetics per se, but are essential components of balanced anaesthesia.

Common agents: Morphine, Fentanyl, Remifentanil, Alfentanil, Sufentanil

Mechanism: Act on mu (μ), kappa (κ), and delta (δ) opioid receptors. Presynaptic: inhibit calcium channels (reduce neurotransmitter release). Postsynaptic: open potassium channels (hyperpolarisation).

Role in anaesthesia:

Analgesia (opioids are the backbone of intraoperative and postoperative pain management)
Blunt the sympathetic response to laryngoscopy and intubation
Reduce MAC of inhaled agents (opioid-sparing effect)

Fentanyl specifics:

Highly lipid soluble → rapid onset (2-3 minutes), short duration (30-60 minutes single dose)
100x more potent than morphine
Minimal cardiovascular effects
Used most commonly in anaesthetic inductions and for procedural analgesia

Remifentanil:

Ultra-short acting (offset in <5 minutes) because it is metabolised by non-specific plasma esterases (NOT liver dependent)
Context-insensitive half-life: does not accumulate with infusion
Ideal for procedures requiring rapid changes in level of analgesia

Opioid adverse effects:

Respiratory depression (most dangerous - dose dependent)
Nausea and vomiting (trigger zone stimulation)
Constipation (decreased gut motility)
Urinary retention
Pruritus (itching, especially with spinal/epidural opioids)
Bradycardia (fentanyl/remifentanil)
Chest wall rigidity (high-dose fentanyl infusion - "wooden chest syndrome")

Reversal: Naloxone - competitive antagonist at all opioid receptor types. Titrate carefully - can precipitate acute pain crisis and sympathetic storm if given too rapidly.

7. NEUROMUSCULAR BLOCKING AGENTS (NMBAs) - Muscle Relaxants

These are NOT anaesthetics but are part of balanced anaesthesia. They provide the "muscle relaxation" component.

How do muscles contract normally?

Motor nerve fires
↓
Acetylcholine (ACh) released from nerve terminal
↓
ACh crosses neuromuscular junction
↓
ACh binds to nicotinic ACh receptors on muscle endplate
↓
Sodium influx → depolarisation → END PLATE POTENTIAL
↓
Muscle ACTION POTENTIAL generated
↓
Muscle CONTRACTS

NMBAs interfere with this process.

Classification:

Type	Example	Mechanism	Duration	Reversal
Depolarising	Succinylcholine (suxamethonium)	Binds ACh receptor and produces PROLONGED depolarisation → fasciculations then paralysis	Short (5-10 min)	No pharmacological reversal (metabolised by plasma cholinesterase)
Non-depolarising	Vecuronium, Rocuronium, Atracurium, Pancuronium, Cisatracurium	Competitive antagonist of ACh receptor - blocks without activating	Variable	Neostigmine (anticholinesterase) + Atropine OR Sugammadex (for rocuronium/vecuronium)

Succinylcholine (Suxamethonium) - HIGH-YIELD:

Phase I block (Depolarising block):

Initial visible muscle fasciculations (whole body twitching briefly)
Then paralysis
Potentiated by anticholinesterases (e.g., neostigmine worsens it)

Phase II block (Desensitisation block):

Occurs with large/repeated doses
The receptors become desensitised/inactivated
Now RESEMBLES a non-depolarising block
Reversed by anticholinesterases (opposite to Phase I)

Adverse effects of succinylcholine:

Hyperkalaemia - depolarisation causes K⁺ release from muscle. In normal patients, small rise. In burns, crush injuries, paraplegia, denervation injuries: MASSIVE K⁺ release → cardiac arrest
Malignant Hyperthermia (MH) - life-threatening complication
Increased intraocular pressure (risk in open eye injuries)
Increased intragastric pressure (risk of aspiration)
Myalgia (muscle pain postoperatively from fasciculations)
Bradycardia (especially with repeated doses, or in children)
Prolonged paralysis in patients with pseudocholinesterase deficiency

Succinylcholine is the DRUG OF CHOICE for Rapid Sequence Induction (RSI) because of its ultra-rapid onset (60 seconds) and short duration - but Rocuronium (1.2 mg/kg) is increasingly replacing it for RSI.

Malignant Hyperthermia (MH) - MUST KNOW:

A pharmacogenetic emergency triggered by:

Succinylcholine
All volatile inhalational agents (halothane, isoflurane, desflurane, sevoflurane)
NOT triggered by propofol, ketamine, opioids, benzodiazepines, N₂O

Mechanism:

Mutation in ryanodine receptor (RYR1) gene (autosomal dominant)
Triggered agents cause uncontrolled calcium release from sarcoplasmic reticulum
Massive sustained muscle contraction and metabolism
Rapid heat production

Features (the "MH picture"):

Rapidly rising temperature (key sign - >40°C)
Masseter spasm (jaw rigidity) - early sign
Rigidity
Rising ETCO₂ (first sign on monitors - body burning oxygen and producing CO₂)
Metabolic acidosis
Hyperkalaemia
Myoglobinuria (dark urine) → acute renal failure
CK markedly elevated

Treatment:

STOP all triggering agents immediately
DANTROLENE - specific antidote. Mechanism: inhibits calcium release from sarcoplasmic reticulum. Dose: 2.5 mg/kg IV bolus, repeat every 5 minutes up to 10 mg/kg
100% oxygen, hyperventilate
Cooling measures
Treat hyperkalaemia, acidosis
IV fluids to protect kidneys

Safe agents for MH-susceptible patients: Propofol, N₂O, ketamine, opioids, all local anaesthetics, all benzodiazepines, all non-depolarising NMBAs

Reversal of Non-Depolarising NMBAs:

Neostigmine + Atropine (or Glycopyrrolate):

Neostigmine inhibits acetylcholinesterase → more ACh at NMJ → overcomes competitive block
But neostigmine also increases ACh at muscarinic receptors (heart, gut) → bradycardia, excessive secretions
Therefore ALWAYS give atropine or glycopyrrolate with neostigmine

Sugammadex:

Revolutionary drug - encapsulates rocuronium and vecuronium molecules in a ring structure → prevents receptor binding → rapid complete reversal regardless of depth of block
No muscarinic side effects (no need for atropine)
Works even in profound block

THE PHASES OF GENERAL ANAESTHESIA IN PRACTICE

1. PREMEDICATION
   Midazolam (anxiolysis, amnesia)
   Atropine (dry secretions, prevent bradycardia)
   Ranitidine/omeprazole (reduce gastric acid)
                ↓
2. INDUCTION
   IV agent: Propofol or Thiopental (rapid LOC)
   Opioid: Fentanyl (blunt laryngoscopy response)
   NMBA: Succinylcholine or Rocuronium (facilitate intubation)
                ↓
3. MAINTENANCE
   Inhalational agent (isoflurane/sevoflurane) + N₂O + O₂
   AND/OR IV infusion (TIVA with propofol ± remifentanil)
   NMBA top-ups as needed
                ↓
4. EMERGENCE
   Stop inhalational agent
   Reverse NMBAs (neostigmine+atropine or sugammadex)
   Patient breathes spontaneously
   Extubate when awake, responding
                ↓
5. RECOVERY
   Monitor in PACU (Post-Anaesthesia Care Unit)
   Manage PONV, pain, shivering

SECTION 3C: LOCAL ANAESTHETICS

What Are Local Anaesthetics?

Local anaesthetics (LAs) are drugs that REVERSIBLY block nerve conduction in a localised area. The patient stays FULLY CONSCIOUS but feels nothing in the blocked area.

Perfect analogy: Imagine a telephone wire. The electrical signal travels through the wire to pass a message. A local anaesthetic is like a clamp placed on the wire that stops the electrical signal from travelling past that point. Remove the clamp (drug wears off) and the signal flows freely again.

MECHANISM OF ACTION

Step by step:

The local anaesthetic molecule (e.g., lidocaine) is injected near a nerve.
Being a weak BASE, at physiological pH (7.4), about half the drug exists as an uncharged (free base, non-ionised) form and half as a positively charged (ionised) form.
The uncharged form is lipid-soluble and crosses the nerve cell membrane easily.
Once inside the cell (where pH is slightly lower), more drug converts to the charged (ionised) form.
The charged form enters the Na⁺ channel from the INSIDE and binds to a specific site on the alpha subunit of the voltage-gated Na⁺ channel.
This binding PREVENTS the channel from opening in response to membrane depolarisation.
Na⁺ cannot enter the cell.
No depolarisation occurs.
The action potential cannot be generated.
No nerve signal passes → no sensation in that area.

The key phrase: "Local anesthetics bind to the alpha subunit of the voltage-gated sodium channel from the inner (cytoplasmic) side and prevent channel activation."

State-dependent block: Local anaesthetics bind PREFERENTIALLY to channels that are OPEN or INACTIVATED (i.e., actively firing neurons). This is called:

Frequency-dependent (or use-dependent) block: Rapidly firing neurons (like pain fibres during an attack) are blocked more easily than resting neurons.

STRUCTURE OF LOCAL ANAESTHETICS

All local anaesthetics have the same three-part structure:

[LIPOPHILIC aromatic ring] --- [INTERMEDIATE CHAIN] --- [HYDROPHILIC amine group]
                                  ↑
                       Ester (–COO–) or Amide (–NHCO–)

This intermediate chain determines whether it is an ESTER or an AMIDE local anaesthetic. This distinction is hugely important clinically.

Simple memory trick: Amide agents have the letter "i" TWICE in their generic name (lidocaine, bupivacaine, mepivacaine, ropivacaine, prilocaine). Ester agents do not follow this pattern (procaine, tetracaine, cocaine, chloroprocaine, benzocaine).

ESTERS vs. AMIDES - The Critical Comparison

Feature	ESTERS	AMIDES
Examples	Procaine, Tetracaine, Cocaine, Chloroprocaine, Benzocaine	Lidocaine, Bupivacaine, Ropivacaine, Mepivacaine, Prilocaine
Metabolism	Plasma pseudocholinesterase (in blood)	Liver (hepatic microsomal enzymes)
Metabolite	PABA (para-aminobenzoic acid)	Non-PABA metabolites
Allergic reactions	More common (PABA is allergenic)	Rare (allergy to true amide extremely unusual)
Stability	Less stable	More stable (longer shelf life)
Duration	Variable	Variable
Cross-allergy	All esters cross-react with each other	Amides do NOT cross-react with esters

Clinical implication: If a patient reports allergy to a local anaesthetic, determine if it was an ester or amide. If allergy is to an ester, you can safely use an amide (no cross-reactivity).

INDIVIDUAL LOCAL ANAESTHETIC DRUGS

1. LIDOCAINE (Lignocaine, Xylocaine)

The gold standard, most versatile LA.

Classification: Amide Onset: Fast (pKa 7.9 - close to body pH = more non-ionised form available = faster onset) Duration: Intermediate (1-2 hours, extended to 2-4 hours with adrenaline) Maximum dose:

Plain: 3 mg/kg (or 200 mg)
With adrenaline/epinephrine: 7 mg/kg (or 500 mg)

Systemic uses of lidocaine:

Antiarrhythmic (Class IB) - used IV for ventricular arrhythmias
Intraoperative antiarrhythmic
Topical for surface anaesthesia
EMLA cream (lidocaine + prilocaine) for skin analgesia

Metabolism: Liver (N-dealkylation to MEGX and GX metabolites)

2. BUPIVACAINE (Marcaine, Sensocaine)

Classification: Amide Onset: Slow (high pKa 8.1 = more ionised at body pH = slower onset) Duration: LONG (4-8 hours, one of the longest acting agents) Maximum dose:

Plain: 2 mg/kg (or 150 mg)
With adrenaline: 3 mg/kg (or 225 mg)

Special property: High lipid solubility and high protein binding (96%) → long duration

Clinical uses:

Spinal anaesthesia (most commonly used spinal LA)
Epidural anaesthesia
Peripheral nerve blocks
Wound infiltration for postoperative analgesia

BUPIVACAINE CARDIOTOXICITY - CRITICAL EXAM TOPIC: Bupivacaine binds to cardiac sodium channels in the INACTIVATED state and has SLOW DISSOCIATION from those channels (unlike lidocaine which dissociates quickly). This means:

Bupivacaine can accumulate in cardiac sodium channels at physiological heart rates
Causes profound cardiac depression (negative inotropy, arrhythmias, conduction block)
Ventricular fibrillation can occur that is VERY DIFFICULT TO RESUSCITATE
Treatment of bupivacaine cardiac toxicity: Intralipid (lipid emulsion) 20% - the fat acts as a "lipid sink" absorbing bupivacaine molecules from cardiac tissue

Racemic bupivacaine vs Ropivacaine: Bupivacaine is a racemate (mixture of R and S enantiomers). The R(+) enantiomer is more cardiotoxic. Ropivacaine and levobupivacaine are PURE S(–) enantiomers and are therefore LESS CARDIOTOXIC.

3. ROPIVACAINE (Naropin)

Classification: Amide, pure S(–) enantiomer Duration: Long (similar to bupivacaine) Advantage over bupivacaine: Less cardiotoxic, has some intrinsic vasoconstrictive properties

Preferred for:

Epidural infusions (labour analgesia - less motor block at analgesic concentrations)
Regional nerve blocks

4. PRILOCAINE (Citanest)

Classification: Amide Special property: Metabolised to ortho-toluidine, which oxidises haemoglobin to methaemoglobin → METHAEMOGLOBINAEMIA

Clinical implication: Do not use in large doses in infants, pregnant women, patients with anaemia or breathing problems, or patients taking oxidant drugs.

Use in EMLA cream: EMLA = Eutectic Mixture of Local Anaesthetic = 2.5% lidocaine + 2.5% prilocaine. Creates a eutectic mixture that is liquid at room temperature and penetrates intact skin.

5. COCAINE

Classification: Ester Unique property: The ONLY local anaesthetic that causes VASOCONSTRICTION. (All others cause vasodilation, hence the use of adrenaline as a vasoconstrictor additive.) Mechanism of vasoconstriction: Blocks norepinephrine reuptake at nerve terminals → accumulation of norepinephrine → vasoconstriction

Uses: Topical anaesthesia for nasal/nasopharyngeal procedures (ENT surgery) - the ONLY LA with both anaesthetic AND vasoconstrictive properties, reducing bleeding.

Toxicity: CNS stimulation, cardiovascular stimulation (hypertension, arrhythmias, MI), addiction potential

6. PROCAINE (Novocaine)

Classification: Ester Historical significance: First synthetic local anaesthetic Onset: Slow, Duration: Short Uses: Spinal anaesthesia (historically), dental anaesthesia Allergy: Produces PABA → common allergy

7. TETRACAINE (Amethocaine, Pontocaine)

Classification: Ester, high lipid solubility Duration: Very long Uses: Spinal anaesthesia, topical anaesthesia (eye drops - proxymetacaine/proparacaine is preferred now)

8. CHLOROPROCAINE (Nesacaine)

Classification: Ester Metabolism: Extremely RAPID hydrolysis by plasma cholinesterase → very short duration Low systemic toxicity because it's broken down so fast Uses: Epidural, rapid-onset situations, obstetric epidurals

PHYSICOCHEMICAL PROPERTIES AND THEIR CLINICAL IMPORTANCE

1. pKa and Onset of Action:

pKa is the pH at which 50% of the drug is ionised and 50% is non-ionised
At physiological pH (7.4), the lower the pKa, the MORE non-ionised (free base) drug is present
More non-ionised drug = MORE drug crossing the membrane = FASTER onset

Why LAs don't work well in infected tissues: Infected tissue has a LOW pH (acidic). At low pH, even more of the LA converts to the ionised form. Less drug can cross the nerve membrane. Nerve block is poor. This is why dentists struggle to anaesthetise an acutely infected tooth.

2. Lipid Solubility and Potency:

Higher lipid solubility = more easily crosses lipid nerve membrane = greater POTENCY
E.g., bupivacaine (lipid solubility 8) > lidocaine (lipid solubility 1)

3. Protein Binding and Duration:

Local anaesthetics bind to proteins inside the Na⁺ channel
Higher protein binding = longer duration
Bupivacaine (96% protein binding) vs Lidocaine (64%)

VASOCONSTRICTORS (ADRENALINE/EPINEPHRINE)

Vasoconstrictors are added to local anaesthetic solutions to:

Reduce absorption of the LA into systemic circulation (by constricting blood vessels)
Prolong duration of action (LA stays at the site longer)
Reduce bleeding at the surgical site
Allow higher doses of LA to be used safely (reduces peak blood levels)

Adrenaline concentration used: 1:200,000 (5 μg/mL)

Contraindications to vasoconstrictors:

End-organ areas where vasoconstriction could cause ischaemia: fingers, toes, nose, ear pinna, penis (the "ring" block areas)
These areas have no collateral circulation - adrenaline can cause tissue death (gangrene)
Thyrotoxicosis
MAO inhibitor therapy
Uncontrolled hypertension

TYPES OF REGIONAL ANAESTHESIA

1. Topical Anaesthesia

Drug applied directly to surface
Examples: EMLA cream (skin), lidocaine spray (throat), cocaine (nose), amethocaine eye drops
No needle required

2. Infiltration Anaesthesia

Drug injected directly into tissue near surgical site
Most common use: wound closure, minor procedures

3. Field Block

Drug injected around the surgical field (like a wall of anaesthesia)

4. Peripheral Nerve Block

Drug injected near a specific nerve trunk
Examples:
- Brachial plexus block (arm surgery)
- Femoral nerve block (knee/thigh)
- Sciatic nerve block (foot surgery)
- Intercostal nerve block (rib fractures)

5. Neuraxial (Central) Blocks:

Feature	SPINAL (Intrathecal)	EPIDURAL
Site of injection	INTO subarachnoid space (CSF)	INTO epidural space (outside dura)
Volume of drug	Small (1.5-4 mL)	Large (10-20 mL)
Onset	Fast (2-5 minutes)	Slower (10-20 minutes)
Block density	Dense (complete sensory + motor)	Variable (can titrate)
Catheter possible?	Usually single shot	YES - catheter for repeated doses
Duration of single shot	Fixed	Variable
Headache risk	PDPH (post-dural puncture headache)	No (dura not punctured)
Level control	Position, baricity of solution	Volume, site of injection
Common drugs	Bupivacaine (heavy), Tetracaine, Lidocaine	Bupivacaine, Ropivacaine + Opioid

Post-Dural Puncture Headache (PDPH):

Occurs after spinal (or accidental dural puncture during epidural)
Mechanism: CSF leaks through the dural puncture → CSF pressure drops → brain "sags" pulling on meningeal vessels → headache
Characteristic: POSTURAL - worse standing/sitting, better lying flat (diagnostic)
Treatment: Bedrest, hydration, caffeine. If severe: BLOOD PATCH (10-20 mL of patient's own blood injected into epidural space to seal the hole)

Total Spinal: If an epidural dose is accidentally given intrathecally → too much drug in CSF → block rises to upper cervical/brainstem level:

Complete paralysis
Severe hypotension (loss of all sympathetic tone)
Apnoea
Treatment: Immediate ventilatory support, vasopressors (ephedrine, phenylephrine)

SYSTEMIC TOXICITY OF LOCAL ANAESTHETICS (LAST - Local Anaesthetic Systemic Toxicity)

When does it occur?

Accidental intravascular injection
Absorption from a highly vascular area
Excessive total dose
In patients with reduced clearance (liver disease, elderly)

Sequence of signs and symptoms (plasma concentration-dependent):

LOW concentration → CNS EXCITATION (because inhibitory neurons are blocked first)
• Perioral tingling and numbness
• Tinnitus (ringing in ears)
• Metallic taste in mouth
• Dizziness, lightheadedness
• Visual disturbances
        ↓
MODERATE concentration → CNS DEPRESSION
• Slurred speech
• Confusion, drowsiness
        ↓
HIGH concentration → CONVULSIONS (generalised tonic-clonic seizure)
        ↓
VERY HIGH concentration → CNS DEPRESSION, COMA, CARDIOVASCULAR COLLAPSE
• Loss of consciousness
• Cardiac arrhythmias, cardiac arrest

Cardiovascular toxicity:

Conduction abnormalities (prolonged PR, widened QRS)
Ventricular arrhythmias
Cardiac arrest
Bupivacaine is the most cardiotoxic (most difficult to resuscitate)

Treatment of LAST:

Stop injection immediately
Call for help
100% oxygen, airway management
Benzodiazepines for seizures (first line)
Intralipid (lipid emulsion 20%) - bolus 1.5 mL/kg IV, then infusion
- The lipid acts as a "lipid sink," absorbing the LA from tissues
- This is now standard in all departments using local anaesthetics
Cardiopulmonary resuscitation if needed

SECTION 4: TEACH USING ANALOGIES

General Anaesthesia Analogies:

Inhalational Agents: "The brain is like a busy city full of traffic (neural activity). Inhalational anaesthetics are like a flood that gradually fills the streets. The extent of flooding is measured by the MAC. A poorly soluble agent (like desflurane) is like water that doesn't soak into the ground - it floods fast and drains fast. A highly soluble agent (like halothane) is like water that soaks into the soil - it takes longer to flood and much longer to drain."

Propofol: "GABA-A receptors are like the brain's brake pedal. Propofol is a mechanic who jams the brake pedal down hard. The brain's electrical activity slows down, and the patient loses consciousness. The brake releases (propofol redistributes) and the patient wakes up."

Ketamine: "Glutamate (NMDA) receptors are the brain's accelerator pedal - they keep everything excited and conscious. Ketamine jams a piece of rubber into the accelerator so it cannot be pressed. The brain's excitatory drive shuts down, producing a trance-like disconnected state."

Thiopental redistribution: "Thiopental waking up is like a wave. You throw a stone (the drug) into a lake (the body). The central lake (brain) gets wet first. But the water spreads to the shallow shores (muscle) then the surrounding land (fat). The central lake dries up quickly as water flows outward - the patient wakes up. But all that water is still in the surrounding land and cannot escape easily (slow metabolism). With repeated stones - you flood everything and the central lake stays wet."

Local Anaesthetics Analogies:

Mechanism: "Voltage-gated sodium channels are like swing gates at a train station. When the train (electrical signal) arrives, the gates open, Na⁺ passengers flood through, and the action potential fires. Local anaesthetics are like glue in the gate mechanism - they stick the gate shut so Na⁺ cannot enter, and the train cannot continue its journey."

pKa and onset: "Think of a local anaesthetic as a key that can only open a lock when it has a certain shape. The non-ionised form is the 'correct shape' that crosses membranes. At body pH, drugs with a lower pKa have more keys already in the correct shape, so they work faster."

Ester vs. Amide metabolism: "Ester anaesthetics are digested by the kitchen (plasma enzymes, right there in the blood). Amide anaesthetics need to be sent to a restaurant (the liver) to be processed. The kitchen is faster but has limited capacity; the restaurant is slower but handles complex processing."

Adrenaline with LA: "LA injected without adrenaline is like releasing a crowd (drug molecules) into a street where taxis (blood vessels) are freely available. They get picked up quickly and leave the street fast. Adding adrenaline (vasoconstrictor) is like closing all the streets to taxis. The crowd stays in the street longer - the LA has a longer effect."

SECTION 5: STEP-BY-STEP CLINICAL REASONING

Case 1: A 45-year-old man needs emergency appendicectomy. He has eaten 2 hours ago.

Step 1: Risk assessment

He has a FULL STOMACH → high aspiration risk
Need Rapid Sequence Induction (RSI)

Step 2: Premedication choices

Sodium citrate (oral antacid) → neutralises gastric acid
Metoclopramide → speeds gastric emptying
Ranitidine/omeprazole → reduces acid production

Step 3: Induction

Pre-oxygenate with 100% O₂ for 3 minutes
Cricoid pressure (Sellick's manoeuvre) → compresses oesophagus to prevent regurgitation
Rapid IV induction: Propofol + Fentanyl
Succinylcholine (1.5 mg/kg IV) for rapid intubation (onset 45-60 seconds)
OR Rocuronium (1.2 mg/kg IV) if succinylcholine is contraindicated

Step 4: Maintenance

Isoflurane or sevoflurane in O₂/air mixture
Additional analgesia: morphine
Check tube position, capnography

Step 5: Emergence

Stop volatiles
Reverse NMBAs: Sugammadex (for rocuronium) OR neostigmine + atropine (for others)
Extubate AWAKE and with intact reflexes (full stomach patient - never extubate deep)
Transfer to recovery

Case 2: A 30-year-old woman needs inguinal hernia repair under spinal anaesthesia.

Step 1: Consent and assessment

Check for contraindications: coagulopathy, infection at site, raised ICP, patient refusal
Check platelet count and INR

Step 2: Patient preparation

IV cannula, monitoring (BP, ECG, SpO₂)
IV fluid preloading (500 mL Normal saline) to prevent hypotension

Step 3: The spinal

Sitting or lateral position
Clean and drape L3-L4 or L4-L5 space (below the conus medullaris at L1)
Spinal needle (25G Whitacre or 27G pencil-point) - small gauge = less PDPH
Confirm CSF return
Inject heavy bupivacaine 0.5% (hyperbaric) 2.5-3 mL

Step 4: Monitor the block

Patient lies flat
Check block level with ice/pin prick
Need T10 level for inguinal surgery
Watch blood pressure - hypotension treated with IV ephedrine or phenylephrine + fluids

Step 5: Postoperative care

Warn patient: may have temporary leg weakness (2-4 hours)
Watch for urinary retention (especially male patients)
Watch for PDPH (onset within 24-48 hours, worse on standing)

Case 3: A patient is allergic to lidocaine. What can you use?

Think through it:

Is it a true allergy or vasovagal/adrenaline response? (Most "allergies" are not true allergies)
If truly allergic to lidocaine (an AMIDE):
- Try another amide - cross-reactivity between amides is EXTREMELY RARE
- Or use an ester (procaine, chloroprocaine) - no cross-reactivity between esters and amides
If allergic to procaine (an ESTER) - avoid all other esters (cross-react via PABA)
- Use an amide safely

Case 4: Patient develops sudden tachycardia, rising temperature, and masseter spasm during halothane anaesthesia.

Think through it:

Triggers: halothane (volatile agent) + succinylcholine → MALIGNANT HYPERTHERMIA
Earliest monitor sign: Rising ETCO₂
First clinical sign: Masseter spasm (jaw rigidity)
Confirm rising temperature (>39°C rapidly)

Action:

Call for help - it is an emergency
Stop halothane IMMEDIATELY
Call for dantrolene (2.5 mg/kg IV bolus, repeat to max 10 mg/kg)
Switch to non-triggering anaesthetic (propofol TIVA)
Hyperventilate with 100% O₂
Cool the patient (cold IV fluids, ice packs)
Treat acidosis (sodium bicarbonate)
Treat hyperkalaemia (calcium, glucose-insulin, salbutamol)
Urine output monitoring (myoglobinuria → renal failure)
ICU postoperatively for monitoring

SECTION 6: MEMORY TOOLS

Mnemonics for Inhalational Agents

SHIN - Haemodynamic effects of volatiles:

Sensitises myocardium to catecholamines: Halothane (only really clinically important)
Isoflurane: coronary steal (controversial)
Malignant hyperthermia: Not triggered by N₂O, propofol, ketamine, opioids, or benzodiazepines

For MAC values (lowest to highest): "Have I Seen Desflurane?"

Halothane: 0.75
Isoflurane: 1.15
Sevoflurane: 2.0
Desflurane: 6-7
N₂O: 105 (always mention it separately as "can never achieve alone")

For blood:gas coefficients (least soluble = fastest): Think "DeSNHa" - from LEAST soluble to MOST:

Desflurane (0.42) - FASTEST
Sevoflurane (0.65)
N₂O (0.47 - actually between these two)
Isoflurane (1.4)
Halothane (2.4) - SLOWEST

Mnemonics for Local Anaesthetics

AMIDE agents - double "i" trick: lidocaine, bupivacaine, mepivacaine, ropivacaine, prilocaine Every amide has the letter "i" twice before the "caine" suffix.

LAST sequence of toxicity: "TM-CS-CVA"

Tingling (lips, tongue)
Metallic taste
Convulsions
Sedation/CNS depression
Cardiovascular collapse
Ventricular arrhythmia
Arrest

The "3, 7 rule" for lidocaine doses:

3 mg/kg without adrenaline
7 mg/kg with adrenaline (adrenaline allows you to use more than double)

Mnemonics for IV Anaesthetics

Propofol adverse effects: "MALE BAD"

Myocardial depression
Apnoea on induction
Lipid emulsion formulation (pain on injection)
Emetic control (antiemetic - actually good)
Bradycardia/hypotension
Allergy (egg/soy - rare)
Dreams, PRIS with prolonged use

Ketamine "UP" features (cardiovascular stimulation): Ketamine RAISES everything:

Up: HR, BP, CO
Up: ICP (contraindicated in head injury)
Up: Bronchodilation (good in asthma)
Up: Salivation
Down the rabbit hole: Dissociation/hallucinations

SAFE agents in porphyria: "PKON"

Propofol
Ketamine
Opioids
N₂O (+ Benzodiazepines, muscle relaxants, local anaesthetics - all safe)
AVOID: Thiopental, All volatile agents (historically - though evidence on volatiles in porphyria is mixed)

SECTION 7: EXAMINER'S CORNER

Most Tested Facts

MAC definition and factors affecting it
Halothane hepatitis - types, mechanism, risk factors
Malignant hyperthermia - triggers, features, treatment with dantrolene
Mechanism of local anaesthetics - sodium channel blockade
Bupivacaine cardiotoxicity and lipid emulsion treatment
Guedel's stages of anaesthesia
Esters vs amides - classification, metabolism, allergy
Succinylcholine - mechanism, fasciculations, phase I vs phase II block, hyperkalaemia, contraindications
Thiopental - contraindication in porphyria, redistribution termination
Ketamine - cardiovascular stimulation, dissociative anaesthesia, NMDA mechanism

Most Likely Essay Questions

"Describe the mechanism of action, pharmacokinetics, adverse effects, and clinical uses of inhalational anaesthetic agents."
"Classify local anaesthetic agents. Describe the mechanism of action and systemic toxicity of lidocaine. What is the management of local anaesthetic toxicity?"
"Write an essay on balanced anaesthesia."
"Describe the pharmacology of propofol."
"What is malignant hyperthermia? How do you manage it?"

Most Likely Short Notes

MAC - definition, factors affecting
Halothane hepatitis
Succinylcholine - mechanism and adverse effects
Difference between spinal and epidural anaesthesia
Dantrolene - mechanism and uses
Lipid rescue (intralipid therapy)
Post-dural puncture headache
Ketamine - cardiovascular effects
EMLA cream
Propofol infusion syndrome

Most Likely Viva Questions

"What is MAC? How does MAC change with age?"
"Which local anaesthetic is used for spinal anaesthesia and why?"
"A patient develops jaw rigidity and rising temperature under halothane. What is your diagnosis and management?"
"Why is thiopental contraindicated in porphyria?"
"What is the antidote for bupivacaine toxicity?"
"Classify neuromuscular blocking agents. What is the difference between succinylcholine and vecuronium?"
"How do local anaesthetics work in an infected tooth?"
"What are the stages of general anaesthesia?"
"Why is adrenaline never used in ring blocks?"

Most Likely MCQs

Drug with highest MAC: N₂O (105%)
Drug with lowest MAC: Halothane (0.75%)
Fastest onset inhalational agent: Desflurane (lowest blood:gas coefficient)
Best for inhalation induction in children: Sevoflurane
Local anaesthetic that causes vasoconstriction: Cocaine
Drug of choice in malignant hyperthermia: Dantrolene
Drug causing halothane hepatitis via immune mechanism: Halothane
Contraindication for thiopental: Porphyria
Antidote for bupivacaine toxicity: Intralipid 20%
Drug causing emergence delirium: Ketamine
LA metabolised by plasma cholinesterase: Ester group (procaine, chloroprocaine)
LA with methaemoglobinaemia risk: Prilocaine
Drug of choice for induction in shock: Ketamine
Succinylcholine phase I block: Enhanced by non-depolarising NMBAs, resistant to neostigmine
First sign of LAST: Perioral tingling and numbness

Common Traps

"Succinylcholine is reversed by neostigmine" - WRONG for Phase I block (neostigmine makes Phase I WORSE). Neostigmine works for Phase II block.
"Local anaesthetic allergy is common" - Most "allergies" are vasovagal or adrenaline reactions. True amide allergy is extremely rare.
"Ketamine depresses cardiovascular system" - WRONG. It STIMULATES. The only anaesthetic induction agent that raises BP and HR.
"Propofol has analgesic properties" - WRONG. Propofol is NOT an analgesic.
"Thiopental wears off due to metabolism" - WRONG for a single dose. It wears off due to REDISTRIBUTION.
"All volatile agents trigger MH" - N₂O does NOT trigger MH.
"Spinal goes above L1" - WRONG. The conus medullaris ends at L1-L2, so inject at L3-4 or L4-5 to avoid cord damage.
"Adrenaline can be used in ring blocks" - ABSOLUTELY WRONG and potentially fatal (gangrene).

SECTION 9: HIGH-YIELD REVISION SHEET

GENERAL ANAESTHETICS: MUST-KNOW FACTS

Drug	Class	Mechanism	Key Fact
Halothane	Volatile	GABA-A ↑	Hepatitis (immune), MH trigger, sensitises to catecholamines
Isoflurane	Volatile	GABA-A ↑	Coronary steal (controversial), least metabolised of older agents
Sevoflurane	Volatile	GABA-A ↑	Best for mask induction, Compound A (renal concern)
Desflurane	Volatile	GABA-A ↑	Fastest onset/offset, sympathetic stimulation with rapid ↑
N₂O	Gas	NMDA ↓	MAC 105%, diffusion hypoxia, B12 inactivation, expand cavities
Propofol	IV	GABA-A ↑	Anti-emetic, PRIS, white emulsion, apnoea on induction
Thiopental	IV Barbiturate	GABA-A ↑	Redistribution recovery, CONTRAINDICATED in porphyria
Ketamine	IV	NMDA ↓	Cardiovascular stimulant, bronchodilator, dissociation, ↑ICP
Etomidate	IV	GABA-A ↑	Most haemostable, adrenal suppression, myoclonus
Midazolam	BZD	GABA-A ↑	Anxiolysis, amnesia, reversed by flumazenil

LOCAL ANAESTHETICS: MUST-KNOW FACTS

Drug	Class	Key Facts	Max Dose
Lidocaine	Amide	Most versatile, antiarrhythmic, EMLA	3 mg/kg (plain), 7 mg/kg (+ADR)
Bupivacaine	Amide	Long duration, CARDIOTOXIC, intralipid reversal	2 mg/kg (plain), 3 mg/kg (+ADR)
Ropivacaine	Amide	Less cardiotoxic than bupivacaine, vasoconstricts	Similar to bupivacaine
Prilocaine	Amide	METHAEMOGLOBINAEMIA risk, in EMLA	6 mg/kg
Cocaine	Ester	ONLY vasoconstricting LA, nasal procedures	1-3 mg/kg
Procaine	Ester	First synthetic, PABA allergy	7 mg/kg
Tetracaine	Ester	Long duration, spinal and topical	1-1.5 mg/kg
Chloroprocaine	Ester	Fastest metabolism, low toxicity	11 mg/kg (+ADR)

EXAM EMERGENCY FACTS (Final 30 Minutes Before Exam)

MAC = alveolar concentration preventing movement in 50% patients to surgical incision
Lowest MAC = Halothane (0.75); Highest MAC = N₂O (105%)
Fastest inhalational agent = Desflurane (lowest blood:gas 0.42)
Best paediatric induction = Sevoflurane (non-pungent)
MH treatment = Dantrolene (inhibits SR Ca²⁺ release)
MH triggers = ALL volatile agents + succinylcholine
MH NOT triggered by = N₂O, propofol, ketamine, opioids, benzodiazepines
Porphyria - AVOID thiopental; USE propofol, ketamine
Bupivacaine toxicity - INTRALIPID 20%
LAST sequence: tingling → metallic taste → convulsions → CVS collapse
Amides = double "i" in name; metabolised by liver
Esters = metabolised by plasma cholinesterase; PABA allergy
Cocaine = only vasoconstricting LA
Prilocaine = methaemoglobinaemia
Ketamine = CARDIOVASCULAR STIMULANT (only one)
Thiopental = redistribution (NOT metabolism) terminates single-dose effect
Propofol = anti-emetic, PRIS with prolonged use
N₂O: diffusion hypoxia at end (give O₂ for 5-10 mins); expands closed cavities; inactivates B12
Succinylcholine Phase I = not reversed by neostigmine (made worse)
Sugammadex = reverses rocuronium/vecuronium encapsulation

SECTION 10: SELF-ASSESSMENT (10 Questions)

Q1: Define MAC. A patient receives isoflurane at 1.5x MAC. What does this mean clinically?

Answer: MAC (Minimum Alveolar Concentration) is the alveolar concentration of an inhaled anaesthetic that prevents movement in 50% of patients in response to a standardised surgical stimulus. Isoflurane has a MAC of 1.15%. At 1.5x MAC (approximately 1.7%), the patient is receiving a concentration that would prevent movement in approximately 95% of patients (MAC95). This means near-certain surgical immobility, though the patient may not be fully unconscious and amnesic at this level alone - opioids and other adjuncts are still used.

Q2: Why does halothane cause liver damage and what are the risk factors?

Answer: Halothane is metabolised (~20%) by hepatic CYP2E1 to two types of metabolites:

Reductive metabolites (low O₂): directly toxic to hepatocytes (Type 1 mild hepatitis)
Oxidative metabolites (trifluoroacetyl chloride): binds to liver proteins forming neoantigens. The immune system attacks these protein adducts (Type 2 severe fulminant hepatitis = "Halothane Hepatitis")

Risk factors for Type 2: repeated exposures at short intervals (6 weeks), middle-aged obese women, family history, prior adverse reaction to halothane.

Q3: A patient is scheduled for day-case surgery. Which inhalational agent would you choose for maintenance and why?

Answer: Desflurane or Sevoflurane would be ideal for day-case surgery. Both have low blood:gas coefficients (Desflurane 0.42, Sevoflurane 0.65), meaning rapid awakening and fast discharge. Desflurane is the absolute fastest but is pungent and requires a special heated vaporiser. Sevoflurane is non-pungent, can be used for induction too, and offers excellent fast emergence. Either is superior to isoflurane or halothane for day-case surgery due to faster cognitive recovery and discharge.

Q4: Why is thiopental absolutely contraindicated in acute intermittent porphyria?

Answer: Acute intermittent porphyria (AIP) is a genetic disorder of haem biosynthesis. Thiopental induces the enzyme delta-aminolevulinic acid (ALA) synthase, which is the rate-limiting enzyme in haem/porphyrin synthesis. This induces the overproduction of porphyrin precursors (ALA and porphobilinogen) that accumulate and cause a porphyric crisis. A crisis manifests as severe abdominal pain, peripheral motor neuropathy (ascending paralysis), psychiatric manifestations, and autonomic instability - potentially fatal. Safe alternatives include propofol, ketamine, and N₂O.

Q5: What is the mechanism of succinylcholine's action and how does it differ from vecuronium?

Answer:

Succinylcholine (depolarising NMBA): Structurally resembles two acetylcholine molecules joined together. It binds to the nicotinic ACh receptor at the neuromuscular junction and causes SUSTAINED depolarisation (does not detach quickly like ACh). This produces initial fasciculations (muscle twitching) followed by flaccid paralysis (cannot repolarise - prolonged depolarisation). Metabolised by plasma pseudocholinesterase.
Vecuronium (non-depolarising NMBA): Competitively blocks the nicotinic ACh receptor WITHOUT activating it. No fasciculations. Reversed by neostigmine (increases ACh) or sugammadex (encapsulates vecuronium).

Q6: Explain how bupivacaine causes cardiac toxicity and how it is treated.

Answer: Bupivacaine blocks cardiac voltage-gated Na⁺ channels in the INACTIVATED state and dissociates from them VERY SLOWLY. This "fast-in, slow-out" kinetics means that at physiological heart rates, bupivacaine accumulates progressively in cardiac channels, leading to conduction block and ventricular arrhythmias (ventricular fibrillation). Standard resuscitation is often ineffective. Treatment: Intralipid (20% lipid emulsion) creates a "lipid sink" in plasma that sequesters bupivacaine molecules, reducing free plasma concentration and allowing dissociation from cardiac channels. Ropivacaine (pure S-enantiomer) has less cardiotoxicity because it dissociates more quickly.

Q7: A dentist cannot anaesthetise an abscessed tooth with lidocaine. Explain why.

Answer: Lidocaine is a weak base with a pKa of 7.9. At physiological pH 7.4, approximately 25% of the drug exists in the non-ionised (free base) form, which can cross the lipid nerve membrane. In an abscess, the surrounding tissue is highly acidic (low pH due to bacterial metabolism and inflammation). At this acidic pH, the equilibrium shifts: even more of the lidocaine converts to its ionised (charged) form, which CANNOT cross the lipid membrane. Very little drug reaches the sodium channels inside the nerve. As a result, the block is incomplete or fails. This is why regional anaesthesia (mandibular nerve block) rather than local infiltration is preferred for infected teeth - by injecting away from the infected site, normal pH allows proper drug uptake.

Q8: What is diffusion hypoxia? When and how does it occur?

Answer: Diffusion hypoxia (Fink effect) occurs at the END of a nitrous oxide anaesthetic. During the procedure, N₂O dissolved in blood equilibrates with alveolar N₂O. When N₂O is suddenly stopped, large amounts of N₂O rapidly diffuse from blood back into the alveoli. This sudden influx of N₂O dilutes the alveolar oxygen concentration, transiently reducing the fraction of inspired oxygen (FiO₂) available - causing brief hypoxia. Prevention: At the end of all N₂O anaesthetics, give the patient 100% oxygen for 5-10 minutes before removing the mask. This washes out the N₂O and prevents hypoxia.

Q9: Compare and contrast spinal and epidural anaesthesia (5 differences).

Answer:

Feature	Spinal	Epidural
Site	Subarachnoid (CSF)	Epidural space (outside dura)
Drug volume	Small (1.5-4 mL)	Large (15-20 mL)
Onset	Fast (5 minutes)	Slow (15-20 minutes)
Block density	Dense, reliable	Variable, can adjust
Catheter	Usually no	Yes (for continuous infusion)
Headache risk	YES (PDPH if dura punctured)	No (dura not punctured)

Q10: What is malignant hyperthermia? Name three triggers, three clinical features, and the specific antidote with its mechanism.

Answer:

Malignant Hyperthermia (MH) is a life-threatening pharmacogenetic disorder where susceptible patients (autosomal dominant mutation in the RYR1 gene - ryanodine receptor) develop uncontrolled skeletal muscle calcium release when exposed to triggering agents.

Three triggers: Halothane, Isoflurane (and all volatile agents), Succinylcholine

Three clinical features:

Rapidly rising body temperature (>40°C)
Masseter spasm (jaw rigidity - often first sign)
Rising end-tidal CO₂ (earliest monitor finding - increased muscle metabolism) Plus: metabolic acidosis, hyperkalaemia, muscle rigidity

Specific antidote: Dantrolene - mechanism: inhibits the ryanodine receptor (RYR1) on the sarcoplasmic reticulum, blocking the uncontrolled release of calcium from SR stores. This stops the runaway muscle hypermetabolism.

Dose: 2.5 mg/kg IV bolus, repeat every 5 minutes up to 10 mg/kg total
Continue until temperature and ETCO₂ normalise

Learning Note compiled from: Morgan and Mikhail's Clinical Anesthesiology 7e, Barash et al. Clinical Anesthesia 9e, and Miller's Anesthesia 10e. All mechanisms, doses, and clinical principles cross-referenced with authoritative anaesthesiology texts.

This complete learning note covers the full MBBS pharmacology curriculum for general and local anaesthetics, from beginner concepts to exam-level mastery. Every mechanism is explained step-by-step, every adverse effect is linked to its physiological cause, and every exam-favourite topic is flagged.

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